The invention is directed to a drug delivery system for delivery of enterally-administered pharmaceuticals to specific locations along the gastrointestinal tract by immediate release (not sustained) of all or most of the drug at the specific location. The drug delivery system has the capability of complete loss of integrity in a very short space of time allowing delivery of virtually all of the drug contained therein at the location of disintegration. The features that allow this capability are a channel-forming coating allowing the controlled entry of liquid into a core and a core capable of absorbing liquid and swelling enough to cause breakage of a coating surrounding the core, the core disintegrating rapidly after the integrity of the coating is breached.
Specific delivery of drugs to a selected target in the gastrointestinal tract is desired for the treatment of a wide variety of diseases and conditions. It is especially desirable to be able to deliver drugs so that they are targeted to, and absorbed at, specific regions of the gastrointestinal tract. Targeting drugs to specific regions along the gastrointestinal tract provides the ability to locally treat gastrointestinal diseases, thus avoiding systemic side effects of drugs or inconvenient and painful direct delivery of drugs. Such specific delivery also potentially increases the efficiency of the drug and enables a reduction of the minimum effective dose of the drug.
Delivery systems based on coatings exist in the art. Some systems have been reported to target particular parts of the body. For example, U.S. Pat. No. 5,593,697 describes a pharmaceutical implant containing a biologically active material, an excipient comprised of at least one water soluble material and at least one water insoluble material, and a polymer film coating adapted to rupture at a predetermined period of time after implantation. In one form, a bilayer film coating forms an impermeable barrier to the drug. An insoluble outer film controls the degree of access of physiological fluid to an inner film that is soluble at physiological pH. By varying the thickness of the outer film, access of the physiological fluid to the inner film, and thus the time before the failure of the inner film occurs, is said to be controlled. Failure of the inner film then permits a swellable excipient (disintegrant) to exert a force on the outer film which then ruptures releasing the core content. In another embodiment, a monolayer film is used. A film coating comprising a mixture of ethylcellulose and a copolymer of glycolic and lactic acid is used. Ethylcellulose is an insoluble polymer and thus when the PLGA polymer in the film hydrolyzes, the film becomes porous and allows release of the drug. The rate of hydrolysis of the PLGA depends on the ratio of lactic-to-glycolic acid in the polymer.
U.S. Pat. No. 4,252,786 describes a controlled release tablet for the administration of medicinal agents over a prolonged period of time. It involves the application of a film comprising a combination of hydrophobic and hydrophilic polymers to an insoluble swelling type delayed release matrix to modify the drug release rate. Initially when the film is intact, the release of the drug contained in the matrix is primarily controlled by diffusion of solvent and solute molecules through the film. As water or gastric fluid permeates through the film, the gummy complex forms in the core and the slight swelling of the complex causes the film to rupture or erode. The release rate is then controlled by the gummy complex. The application of a relatively water-insoluble water-permeable film primarily controls the drug release rate while the matrix gel is being generated and it is reported that this generates a smoother, gradual, more uniform, release rate during the period of about 8-12 hours, approaching a zero order release pattern.
U.S. Pat. Nos. 5,260,069 and 5,472,708 describe a dosage form for delivering drugs, and particularly drugs that cannot be released by diffusion through a porous coating, such as water insoluble drugs. Pellets are provided in a unit dosage form such as a capsule or tablet. The pellets are composed of a core containing the drug and swelling agent which expands in volume when exposed to water. The core is enclosed within a membrane or coating that is permeable to water. The membrane is composed of a water insoluble but permeable film forming polymer, a water soluble film forming polymer and a permeability reducing agent. Water diffuses through the coating and into the core. As water is taken up by the swelling agent the core expands, exerting force on the coating until it bursts, releasing the drug. The permeability reducing agent reduces the rate at which water reaches the swelling agent, thereby delaying release time. The water soluble polymer dissolves, weakening the coating so that it bursts sooner. By varying the proportions of the three coating ingredients and/or coating thickness, the release timing is reported to be effectively controlled.
U.S. Pat. No. 4,897,270 describes a pharmaceutical tablet comprising a tablet core and a film coat to mask the taste of the core. The core disintegrates immediately following rupture of the film coat. The film coat allows a permeation of moisture to the core which ruptures very rapidly upon contact with gastrointestinal fluid. Thus the core immediately disintegrates, allowing dispersion and dissolution of the drug.
U.S. Pat. No. 5,204,121 describes a drug release system in pellet form where the pellets consist of a core containing the active compound. The core is surrounded by a polymer-containing jacket and a undigestible lacquer layer that is permeable to water. The outer lacquer layer does not dissolve but carries water to the migration controlling jacket layer which then brings the liquid in contact with the drug containing core.
U.S. Pat. No. 4,891,223 describes compositions for the sustained release of a pharmaceutical, comprising a drug-containing core, a first coating containing a polymer swellable upon penetration of the surrounding media, and a second coating, enveloping the first coating, comprising a polymer that is water-soluble and that forms a semi-permeable barrier. The outer coating permits diffusion of the media, into the first coating and then diffusion of the dissolved drug into the surrounding media. The second coating must have requisite stretchability to prevent rupture of a second coating due the swelling of the first coating until a specific time in the release pattern.
U.S. Pat. No. 4,327,725 describes a variation of a basic osmotic device for drug release. The structure of the device is an active agent enclosed in a hydrogel layer that is enclosed in a semi-permeable membrane. The semi-permeable membrane allows diffusion of external fluid but does not allow diffusion of the solution of active agent to the surrounding environment. The hydrogel swells with absorption of external fluid and exerts pressure on the solution of active agent in the external fluid. The solution of the active agent in the external fluid is then delivered to the surrounding media through a single specially constructed passageway through the hydrogel layer and the membrane.
Delivery of Drugs in the Alimentary Canal
The targeting of drugs to desired locations in the alimentary canal can be complicated. Various factors must be taken into consideration for delivery to desirable areas of the alimentary canal. Each segment of the alimentary canal has distinct features which may hinder or favor permeation of drugs across the membrane. The following characteristics are to be taken into account:
1. Anatomicxe2x80x94Surface area, epithelium, presence of mucus cells, venous drainage, lymphatic drainage;
2. Physiologic featuresxe2x80x94absorption pathways, pH, motility and transit time, enzymes;
3. Biochemical featuresxe2x80x94endogenous secretion, pH, gut flora, enzymes;
4. Mechanical featuresxe2x80x94mucus and water coating layers and their turnover rate;
5. Immunological featuresxe2x80x94antigenic stimulation at the epithelial surface.
In the controlled release systems currently known in the art, drugs are released by diffusion and erosion throughout the gastrointestinal tract. Upon arrival at a target site a large portion of the drug may have already been released, leaving only a small portion of the drug for local delivery, or may pass through the site unreleased to a significant degree.
Delivery to the Stomach
Current techniques for targeting drugs to the stomach are based on the understanding that peroral sustained-release and controlled-release may be limited in duration by gastrointestinal transit time, which is closely related to the rate of gastric emptying. Approaches for the prolongation of gastric retention time, include incorporation of fatty acids to reduce physiological gastric emptying (Groning R., et al., Drug Dev. Ind Pharm, ID:527-39 (1984)) and the use of bioadhesive polymers. Such systems have been developed using polymers such as polycarbophyll, sodium carboxymethylcellulose, tragacanth gum, acrylates and methacrylates, modified celluloses and polysaccharide gums (Smart, J. D., et al., J. Pharm. Pharmacol. 36:295 (1984)).
Another system for targeting drugs to the stomach while avoiding gastric emptying is known as a hydrodynamically balanced system. This system is based on capsules or tablets with bulk density lower than gastric fluid. Thus, the dosage form stays buoyant in the stomach. These dosage forms are comprised of 20-75% of one or more hydrocolloids (e.g., hydroxyethylcellulose and hydroxypropylmethylcellulose (Sheth, P. R., Drug Dev. Ind. Pharm. 10:313-39 (1983); Chien, Y. W., Drug Dev. Ind. Pharm 9:1291-330 (1983); Desai, S. and Bolton, S., Pharm. Res. 10: 1321-5 (1993)).
Banakar (Amer. Pharm. 27: 39-48 (1987)) describes gastroinflatable delivery devices. The devices contain one or several inflatable chambers which are filled with gas at body temperature (e.g., a gasifying liquid or a gas-forming solid, such as bicarbonate or carbonate). The chambers are incorporated within a plastic matrix and encapsulated in gelatin. Dissolution of the gelatinous coating inflates the device and drug diffusion occurs.
Certain of the se devices include osmotic pressure compartments containing osmotically active salts. Dissolution of these salts by the gastric fluid pumps out the drug. Others are based upon a floating bilayer compressed matrix. (Ugani, H. M., et al., Int. J. Pharmaceut. 35:157-64 (1987). One of the layers is comprised of a hydrophilic polymer and a carbon dioxide-generating composition. The carbon dioxide maintains buoyancy and the other hydrophilic layer releases the drug from the matrix.
A further method for gastric drug targeting involves an intragastric retention shape, made of polyethylene or polyethylene blend (Cargill, R., et al., Pharm. Res 5:533-536 (1988); Cargill, R., et al., Pharm. Res. 5:506-509 (1989)).
Delivery to the Small Intestine
Delivery of drugs to sites beyond the stomach is especially desirable for drugs that are destroyed by the acid conditions or enzyme of the stomach, or for drugs that cause local irritation in the stomach. Mechanisms for targeting drugs to the stomach are applicable to the delivery of drugs to the upper small intestine. However, targeting to other areas of the small intestine involves several additional systems. The low stomach pH and presence of gastric enzymes have led forms in which the drug is provided with an enteric coating. This coating protects the gastric mucosa from drug irritation. Coating is done with a selectively insoluble substance, and protects drugs from inactivation by gastric enzymes and/or low pH.
The most common enteric coatings are methacrylic acid copolymers (Eudragits(trademark)), cellulose acetate phthalate, cellulose acetate succinate, and styrol maleic acid co-polymers (Ritschel, W. A., Angewante Biopharmazie, Stuttgart (1973), pp. 396-402; Agyilirah, G. A., et al., xe2x80x9cPolymers for Enteric Coating Applicationsxe2x80x9d in Polymers for Controlled Drug Delivery, Tarcha, P. J. ed., CRC Press, (1991) Boca Raton, pp. 39-66). The most significant drawback of enteric coating is the variability in gastric emptying time. This results in a large variance in blood drug levels.
Another method of drug targeting to the small intestine is drug absorption via the lymphatic system. Capillary and lymphatic vessels are permeable to lipid-soluble compounds and low molecular weight moieties (Magersohn, M., Modern Pharmaceutics, Marcel Dekker, New York (1979), pp. 23-85) (Ritschel, W. A., Meth Find Ex. Clin. Pharmacol 13(5):313-336 (1991)). Macromolecules, such as peptides, are absorbed into the lymphatics through Peyer""s patches, which occur equally throughout all segments of the small intestine. Peyer""s patches are most prevalent in young individuals and are characterized by age-related disappearance (Comes, J., Gut 6:230 (1965)).
At the Peyer""s patches, the antigens are processed for presentation to regulatory T cells. The activated T cells migrate to the inflamed tissue, wherein suppressor cytokines neutralize T cells and any other inflammatory cells. This method is presently undergoing investigation (Ermak, T. H., et al., xe2x80x9cStrategies for Oral Immunization and Induction of Gastric Immunityxe2x80x9d in Proceed. Intern. Symp. Control. Rel. Bioact. Mater. 22: 334 (1995)). The major drawback of targeting drugs/peptides to Peyers patches in their reduced availability beyond middle age (Andreasen, Acta Patrol. Microbiol. Scan. 49 (suppl):81 (1943)). Therefore, they provide a target site for absorption until middle age. Targeting the Peyer""s patches in a particular segment of the small intestine can be useful in limiting destructive side reactions. The lymphatic drainage of the small intestine provides an adsorptive window and has promoted design of delivery systems directed at this window (Norimoto et al., Int. J. Pharm. 14:149-157 (1983)).
Another approach for targeting drugs to the small intestine involves the use of intestinal sorption promoters. Studies have been carried out using long chain fatty acids, including linoleic acid, acylcarnitines, and palmitocamitine (Morimoto, K., et. al., Int. J. Pharmaceut. 14: 49-57 (1983); Fix, J. A., et. al., Aires J. Physiol. 14:G-332-40 (1986)).
Bioadhesives have also been used to prolong intestinal transit, as in buccal delivery systems. The adhesion to the intestinal mucosa takes place either by mechanical interlocking or other mechanisms (Longer, M. A., et. al., Pharm. Int. 7:114-7 (1986)).
Excipients for prolongation of GI transit time are also under development. Triethanolamine myristate has been shown to increase the gastrointestinal transit time and improve the absorption of riboflavine (Gronig, R. and Heun, G., Drug Dev. Ind. Pharm. 10:527-539 (1984); Palin, K. J., et al., Int. J. Pharm. 19:107-127 (1984)).
Most small intestinal-specific delivery systems are still experimental except for enteric-coated tablets. However, as discussed above, enteric coating cannot provide reproducible blood levels of drug. Thus, there is a need for a system that targets delivery of a desired agent to the small intestine.
Delivery to the Colon
Because of its location at the distal portion of the alimentary canal, the colon is particular difficult to access. Enteric coating has been used to bypass absorption in the stomach and deliver the drug to the small intestine. Delivery is based upon the pH differences between these two parts of the alimentary canal (Ritschel, W. A. Angewndte Biopharmazio, Stuttgart Wissensec. Verlag (1973), pp 396-402; Agyilirah, G. A. and Banker, G. S., xe2x80x9cPolymers for Enteric Coating Applicationsxe2x80x9d in Polymers for Controlled Drug Delivery, Tarcha, P. J., ed., CRC Press (1991) Boca Raton, pp.39-66). However, it has been demonstrated that the blood levels of enteric dosage forms are variable and erratic due to differences in gastric emptying rate. Also, enteric coatings do not allow for drug targeting to a particular part of the small intestine in a reproducible manner (Kenyon, C. J., et al., Int. J. Pharm. 112:207-213 (1994); Ashford, M., et al. Int. J. Pharm. 91:241-245 (1993)).
In current techniques for targeting drugs to the colon, solid formulations of the desired drug molecules are coated with a pH-resistant polymeric coating. Such formulations are similar to enteric coated formulations which may be used to deliver drugs to the distal ileum. Enteric coatings include bioerodible polymers such as shellac and cellulose acetate phthalate. (Levine et al., Gastroenterology 92:1037-1044 (1987)).
In contrast to the enteric coated formulations, however, the formulations for colonic delivery are designed to withstand both low and slightly basic pH values (around seven) for several hours. During this time, they are assumed to pass the stomach and the small intestine and reach the large intestine, where the coat disintegrates and the drug release process is initiated. In this way, drugs such as 5-amino salicylic acid (5-ASA), and some steroids have been delivered to the colon. The polymers used for this purpose are commonly acrylic acid derivatives or cellulose derivatives such as cellulose acetate phthalate, or ethyl cellulose (Rasmussen, S. N., et al., Gastroenterology 83:1062 (1982); Levine, D. S., et al., Gastroenterology 92:1037 (1987); Mardini H., et al., Gut 28:1084-1089 (1987)).
However, an important limitation of this technique is the uncertainty of the location and environment in which the coat starts to degrade. Depending upon the gastrointestinal motility pattern, which can vary widely in individual patients and in different disease states, degradation of the coating can occur deep in the colon, or within the small intestine.
The presence of short chain fatty acids, carbon dioxide, and other fermentation products, and residues of bile acids, often reduce the pH of the colon to approximately six (Stevens, C. E., Amer. J. Clin. Nutr. 31:S161 (1978); McNeil, N. I., et al., Gut 28:707 (1987)). This change in pH calls into question the reliance on higher colonic pH as a trigger.
The ability of the colonic flora to degrade substrates that are resistant to small bowel digestion has been studied as an alternative method for colonic delivery of drugs. This principle was utilized to deliver laxative products, mainly sennoside and related compounds (Fairbairn, J. W., J. Pharm. Pharmacol. 1:683 (1949); Hardcastle, J. D., et al., Gut 11:1038 (1970); Cummings, J. H., Gut 15:758 (1974)).
A drug traditionally used in the treatment of inflammatory bowel disease is sulfasalazine. Sulfasalazine is composed of the antibacterial sulfapyridine linked to the anti-inflammatory 5-ASA with an azo bond. The 5-ASA is responsible for the clinical effect (Khan, A. K., et al., Lancet 2:892 (1977)). The sulfasalazine is a prodrug which carries the active 5-ASA to the colon, where bacterial azo reduction releases the molecule with the desired therapeutic properties (Klotz, U., Clin. Pharmacokin. 10:285 (1985)). With the 5-ASA prodrugs (sulfasalazine, azodisalicylate and salicylazobenzoic acid), release of the parent drug is mediated by bacterial enzymes located at the target organ, rather than by enzymes of the target tissues. However, the azo compound is potentially toxic.
In U.S. Pat. No. 5,525,634, a delivery device is disclosed that contains a drug in combination with a matrix. The matrix contains a saccharide-containing polymer. The matrix-drug combination can be coated or uncoated. The polymer can be resistant to chemical and enzymatic degradation in the stomach and susceptible to enzymatic degradation in the colon by colonic bacteria. Whether the matrix is resistant or not to chemical and enzymatic degradation in the stomach, the mechanism of release of drug in the colon is by degradation of the matrix by colonic bacteria and the release of the drug embedded in the matrix as a result of the degradation of the matrix by colonic bacterial enzymes.
European patent 485840 (to Rxc3x6hm GmbH), the application for which was published May 20, 1992, discloses a gastrointestinal delivery device containing, as a coating, a mixture of a polysaccharide and Eudragit(trademark). However, this formulation does not allow control of the rate of liquid entry into the formulation. Therefore, control of the site of release of the drug cannot be achieved. Further, the polysaccharide is not provided in particulate form.
WO97/25979 describes a drug-delivery device that allows targeting to various parts of the gastrointestinal tract. A core containing a drug is coated with a hydrophobic polymer which contains hydrophilic, non-water-soluble particles embedded therein. These particles serve as channels for aqueous medium entering the core and for the release of drugs by diffusion through these channels. This delivery system can target various parts of the gastrointestinal tract and slowly release its drug load.
U.S. Pat. No. 4,627,850 (Deters et al.) discloses an osmotic capsule for the controlled rate delivery of a drug comprising outer and inner walls each formed of a different polymeric material, the inner wall defining a space containing the drug, with a passageway through the walls connecting the exterior of the outer wall with the interior of the inner wall.
U.S. Pat. No. 4,904,474 (Theeuwes et al.) discloses a colonic drug delivery device comprising means for delaying the delivery in the drug and in the small intestine and means for delivering the drug in the colon. This device comprises osmotic means for forcing the active pharmaceutical agent out from the compartment in which it is contained through an exit provided in said compartment, into the colon. The means for delaying delivery in the stomach or in the small intestine are pH-resistant coatings. The delay in delivery of the drug is time-based. The structure is so calculated that the contents of the inner drug-filled space are not forced out before the device has reached the preselected target region of the gastro-intestinal tract.
While there is evidence that certain proteins and peptides such as interleukin-II, interferon, colony-stimulating factor, tumor necrosis factor, and melanocyte-stimulating hormone may create new and effective therapies for diseases that are now poorly controlled, the acceptance of these proteins as drugs is currently limited by the methods of delivery. Colonic delivery may be a preferred route of administration for these and other new protein and peptide drugs. In addition, colonic delivery is also important for targeting drugs for the treatment of inflammatory bowel disease and ulcerative colitis. Treatment methods for other disease states of the colon could benefit from the immediate release of a drug in the colon. Severe constipation, whether idiopathic or caused by drugs (e.g. morphine, dopamine) or by disease states (e.g. Parkinson""s, spinal chord injury, multiple sclerosis, diabetes mellitus) are often caused by dysfunction of colonic motility (Sarna, S. K., Digest. Dis. and Sci. 36:827-882 (1991); Sarna, S. K., Digest. Dis. and Sci. 36:998-1018 (1991)). These conditions are not satisfactorily treated by available laxative drugs.
Dysfunction of colon motility may be characterized by (i) inability of the colonic motor activity to propel fecal content into the caucad direction (colonic inertia or gastroparesis); and (ii) inability of the colonic motor activity to provide the propulsive force at the time of defecation (colonic pseudo-obstruction).
In most of the cases the dysfunction in the colonic motility originates in neurological disorders. Therapy in these cases should therefore be directed towards improving the transit of intraluminal contents, by modulating the neural control systems. Prokinetic agents are agents that enhance the transit of material through the GI tract. They affect the GI motility by action at specific cellular drug-receptor interactions, may interfere with the release of one or more mediators affecting GI motility, such as acetylcholine or dopamine, or may act directly on the smooth muscle. As a result, GI motility can be stimulated by dopamine antagonists, such as metoclopramide and domperidone, orby substances which enhance acetylcholine release, such as metoclopramide and cisapride, or by substances that directly bind to muscarinic receptors on the smooth muscle, such as bethanecol. These agents, however, were found to cause neuroendocrine side effects or to accelerate colonic transit with no consistent increase in the frequency of evacuations.
Reversible inhibitors of acetylcholinesterase, such as neostigmine and its salts, physostigmine and its salts and pyridostigmine bromide, have been shown to increase motility of the colon and to cause defecation and even diarrhea when administered intravenously or orally (Kreis, M. E. et al., Gastroenterology 114:S0128 (1998); Ponevc R. J., et al., Gastroenterology 114:G0140 (1998); Turegano-Fuentes, F., et al., Dis. Colon Rectum 40:1353-1357 (1997); Stephenson, B. M., et al., The Lancet 342:1181-1182 (1993); Keeler, J. R., et al., J. Am. Med. Assoc. 266:693-695 (1991); Sadjapour, K., J. Am. Med. Assoc. 249:1148 (1983); Anderson, N. E., et al., Neurology 47:985-987 (1996); Battle, W. M., et al., Gastroenterology 79:1217-1221 (1980)). It is, however, not advantageous to administer these drugs systemically since they affect the smooth muscles of the entire body giving unacceptable side effects. Oral administration is also problematic because of erratic bioavailability and the possibility of the drugs causing side effects earlier in the gastrointestinal tract (Breyer-Pfaff, U., et al., Clin. Pharmacol. Ther. 3 7:495-501 (1985); Aquilonius, S. M., et al., Eur. J. Clin. Pharmacol. 18:423-428 (1980)).
There is also a need for delivery to the colon of drugs that are reported to be absorbable in the colon, such as, inter alia, steroids and xanthines. This would increase the efficiency and enable reduction of the required effective dose (Godbillon, J. et al., British Journal of Clinical Pharmacology 19:113S (1985); Antonin, K. et al., British Journal of Clinical Pharmacology 19:137S (1985); Fara, J. W., Third International Conference on Drug Absorption, Edinburgh (1988)). Propranolol, oxyprenolol, metropolol, timolol, and benazepril are known to be preferentially absorbed in the jejunum while cimetidine, flrosemide, hydrochlothiazide, and amoxicillin are known to be preferentially absorbed in the duodenum. For a review, see Rubinstein, A., Biopharm. Drug Dispos. 11:465-475 (1990).
The currently available enterally administered preparations of drugs designed for colonic delivery are not feasible for long-term use in humans, in part because of the potential toxicity of the azo compounds. There exists a need for an improved colonic delivery system that can be used with a wide variety of drugs and bioactive compounds. Especially, there exists a need for the delivery of drugs such as the above-mentioned drugs and other prokinetic drugs, to the colon and for their release therein in an immediate fashion to treat constipation. Such delivery should be advantageous in that it will allow delivery of the drug to the site of action thereby allowing the use of low doses and avoiding both the problems of bioavailability, of systemic side effects, and of local side effects in the upper gastrointestinal tract.
Thus, there is a need for an immediate delivery version of a targeted delivery system. Immediate delivery would provide an advantage where a high concentration of the drug is necessary for a relatively short period of time, whether for clinical reasons or to effect a concentration-driven gradient to enhance absorption.
The invention is directed to a delivery system or device for targeted delivery to one or more specific location in the alimentary canal. The delivery system or device contains a core and a coating. The core contains a drug in combination with a carrier material. This carrier material has the property of swelling upon contact with an aqueous medium such as that found in the alimentary canal. Thus, the core has the essential characteristics of the capability of absorbing a large amount of aqueous medium and of swelling considerably. However, the core has the further essential characteristic of disintegrating rapidly after the coating is broken. Thus, the coating used for the invention prevents drug release until the predetermined time when particulates in the coating have swollen enough to allow entry of aqueous medim into the core. The core swells and bursts the coating. The unveiled core then disintegrates, releasing its drug load.
Accordingly, in a first embodiment, the core provides the following components: a water insoluble polymer that swells considerably but does not form a strong gel (i.e., hydrogel), a disintegrant, and a hardness enhancer.
Useful water insoluble polymers include, but are not limited to, an insoluble metal salt of a polysaccharide such as calcium pectinate or calcium alginate, or a heavily cross-linked polysaccharide such as glutaraldehyde-cross-linked guar gum, pectin, alginic acid, or other vegetable gum. In preferred embodiments, calcium pectinate is the water insoluble polymer.
Useful disintegrants include, but are not limited to, Crospovidone. Other disintegrants are known in the art.
Useful hardness enhancers include, but are not limited to, microcrystalline cellulose.
In a preferred embodiment, the form of the core includes tablets and pellets, especially compressed tablets and matrix tablets.
The coating comprises a material that is not soluble, or minimally soluble, in aqueous solution, within which material a hydrophilic, non-water-soluble, particulate is embedded. The essential features of the coating are a relatively rigid hydrophobic polymer, embedded with particles of an insoluble hydrophilic polymer that allow entry of water in a controlled fashion. The particles preferably have the ability to swell. The coating serves to control the rate of liquid entry into the tablet. Factors that influence the rate of liquid intake are the weight percent of hydrophilic particles, the size of the particles, the swelling characteristics of the particles, and the degree of hydrophilicity. The core can also influence the rate of water intake for a given coating thickness. A relatively high concentration of water soluble salts in the core (relative to the outside of the tablet) causes a high osmotic gradient across the coating membrane, enhancing uptake of liquid.
This design allows the controlled introduction of water or aqueous medium, such as in the gastrointestinal tract, into the device. When the aqueous medium contacts the particulate matter, the particulate matter swells. The particles eventually form channels from the outer part of the device to the core containing the drug. The core imbibes fluid and then swells, breaks the coating, disintegrates, and all or most of the drug is released with a burst effect.
The core may be designed with varying rates of swellability, e.g., rapid swelling, moderately rapid, slow, etc.
Accordingly, the location of drug release is controlled by varying specific parameters such as the thickness of the outer coating, the amount of particulate embedded in the coating, the type of particulate embedded in the coating, the particle size distribution of the particulate embedded in the coating, the core carrier, the rate of core swelling, swellability of the particulate matter in the coating, hydrophilicity of the particulate matter in the coating, rate of core swelling, and salt concentration in the core.
Thus, the drug delivery system of the invention further provides a method for enterally administering a drug or other bioactive compound to a patient in need of such drug whenever it is necessary or desired that such drug be specifically provided locally in the gastrointestinal tract. In the invention, the drug is not released solely through channels created in the coating, but is released in a burst by a predetermined time at which the coating will be broken and tablet disintegration with simultaneous release of all or most of the drug occurs.
The invention is thus useful for local or targeted delivery of a drug where slow release is undesirable or where a high-peak concentration is necessary. It is also advantageous to improve the absorption of poorly absorbed drugs by providing a strong concentration gradient across the lumen at a point considered to be suitable, whether in the small intestine or in the colon, although in preferred embodiments the site of drug release is the colon.
The preferable areas of treatment include, but are not limited to, the ileum and the colon.
The drug delivery system further provides a method for delivering efficacious levels of one or more drugs designed for local treatment of diseases of particular areas of the alimentary tract. These diseases include, but are not limited to, Crohn""s disease, colitis, irritable bowel syndrome (IBS), local spasmolytic action, ulceration of the mucosa, diarrhea, constipation, polyps, carcinomas, cysts, infectious disorders, and parasitic disorders. The drug delivery system further provides a method for oral immunization through either the Peyer""s Patches or through the colon.
The drug delivery system further offers the opportunity for targeting the local delivery of agents for photodynamic therapy.
The drug delivery system also provides a method for the systemic delivery of efficacious levels of drugs through a targeted area of the alimentary canal. Drugs that are better absorbed, and/or show lesser side effects, in the distal parts of the alimentary canal can be directed to those sites. The delivery system allows delivery to the duodenum,jejunum, ileum, ascending colon, transverse colon, and descending colon as the site for systemic drug delivery.
The invention further provides methods for the preparation of the drug delivery system. The preferred method of preparation is by the preparation of a suspension of the hydrophilic, water-insoluble particulate in an alcoholic solution of a hydrophobic polymer. This suspension is spray coated onto the core tablet or capsule using conventional pan coating technology.